Sengupta Shinjinee, Maji Samir K, Ghosh Santanu K
Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, India.
Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, India
Mol Cell Biol. 2017 Aug 28;37(18). doi: 10.1128/MCB.00118-17. Print 2017 Sep 15.
Loss of p53 function is largely responsible for the occurrence of cancer in humans. Aggregation of mutant p53 has been found in multiple cancer cell types, suggesting a role of aggregation in loss of p53 function and cancer development. The p53 protein has recently been hypothesized to possess a prion-like conformation, although experimental evidence is lacking. Here, we report that human p53 can be inactivated upon exposure to preformed fibrils containing an aggregation-prone sequence-specific peptide, PILTIITL, derived from p53, and the inactive state was found to be stable for many generations. Importantly, we provide evidence of a prion-like transmission of these p53 aggregates. This study has significant implications for understanding cancer progression due to p53 malfunctioning without any loss-of-function mutation or occurrence of transcriptional inactivation. Our data might unlock new possibilities for understanding the disease and will lead to rational design of p53 aggregation inhibitors for the development of drugs against cancer.
p53功能的丧失在很大程度上导致了人类癌症的发生。在多种癌细胞类型中都发现了突变型p53的聚集，这表明聚集在p53功能丧失和癌症发展中起作用。最近有人推测p53蛋白具有类朊病毒构象，尽管缺乏实验证据。在此，我们报告，人类p53在暴露于含有源自p53的易于聚集的序列特异性肽PILTIITL的预形成纤维时会失活，并且发现这种失活状态在许多代中都是稳定的。重要的是，我们提供了这些p53聚集体类朊病毒传播的证据。这项研究对于理解由于p53功能异常而导致的癌症进展具有重要意义，而这种异常并没有任何功能丧失突变或转录失活的发生。我们的数据可能为理解这种疾病开启新的可能性，并将导致合理设计p53聚集抑制剂以开发抗癌药物。
